KEGG   PATHWAY: eju04910
Entry
eju04910                    Pathway                                
Name
Insulin signaling pathway - Eumetopias jubatus (Steller sea lion)
Description
Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.
Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
Class
Organismal Systems; Endocrine system
Pathway map
eju04910  Insulin signaling pathway
eju04910

Organism
Eumetopias jubatus (Steller sea lion) [GN:eju]
Gene
114220406  insulin [KO:K04526]
114200877  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
114210848  IRS1; insulin receptor substrate 1 [KO:K16172]
114196636  IRS2; insulin receptor substrate 2 [KO:K07187]
114214389  insulin receptor substrate 1-like [KO:K17445]
114198362  IRS4; insulin receptor substrate 4 [KO:K17446]
114224308  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
114224631  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
114226659  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
114213130  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
114205617  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
114206954  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
114215744  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
114203265  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114203268  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
114206518  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114215523  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
114214730  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
114216642  GYS2; glycogen [starch] synthase, liver isoform X1 [KO:K00693] [EC:2.4.1.11]
114199538  GYS1; glycogen [starch] synthase, muscle [KO:K00693] [EC:2.4.1.11]
114219135  PPP1CC; serine/threonine-protein phosphatase PP1-gamma catalytic subunit isoform X1 [KO:K06269] [EC:3.1.3.16]
114220523  PPP1CA; serine/threonine-protein phosphatase PP1-alpha catalytic subunit [KO:K06269] [EC:3.1.3.16]
114205825  PPP1CB; serine/threonine-protein phosphatase PP1-beta catalytic subunit [KO:K06269] [EC:3.1.3.16]
114217978  PPP1R3E; protein phosphatase 1 regulatory subunit 3E [KO:K07189]
114210563  PPP1R3A; protein phosphatase 1 regulatory subunit 3A [KO:K07189]
114196777  PPP1R3B; protein phosphatase 1 regulatory subunit 3B isoform X1 [KO:K07189]
114205331  PPP1R3C; protein phosphatase 1 regulatory subunit 3C [KO:K07189]
114197931  PPP1R3D; protein phosphatase 1 regulatory subunit 3D [KO:K07189]
114216719  PPP1R3F; protein phosphatase 1 regulatory subunit 3F isoform X1 [KO:K17453]
114214357  PHKG1; phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform [KO:K00871] [EC:2.7.11.19]
114214412  PHKG2; phosphorylase b kinase gamma catalytic chain, liver/testis isoform [KO:K00871] [EC:2.7.11.19]
114207484  PHKA1; phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform isoform X1 [KO:K07190]
114199371  PHKB; phosphorylase b kinase regulatory subunit beta [KO:K07190]
114223602  PHKA2; phosphorylase b kinase regulatory subunit alpha, liver isoform isoform X1 [KO:K07190]
114209406  calmodulin-like [KO:K02183]
114209774  CALM2; calmodulin-2 [KO:K02183]
114217752  calmodulin-like [KO:K02183]
114217770  LOW QUALITY PROTEIN: calmodulin-like protein 3 [KO:K02183]
114218775  calmodulin-like [KO:K02183]
114213217  CALML6; calmodulin-like protein 6 [KO:K02183]
114197096  CALM3; calmodulin-3 [KO:K02183]
114197118  calmodulin-like [KO:K02183]
114204978  CALM1; calmodulin-1 [KO:K02183]
114206437  CALML4; calmodulin-like protein 4 isoform X1 [KO:K02183]
114224509  PYGB; glycogen phosphorylase, brain form isoform X1 [KO:K00688] [EC:2.4.1.1]
114212728  PYGL; glycogen phosphorylase, liver form isoform X1 [KO:K00688] [EC:2.4.1.1]
114220481  PYGM; glycogen phosphorylase, muscle form [KO:K00688] [EC:2.4.1.1]
114219342  PDE3B; cGMP-inhibited 3',5'-cyclic phosphodiesterase B isoform X1 [KO:K13296] [EC:3.1.4.17]
114208397  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
114197723  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
114199939  PRKAR1B; cAMP-dependent protein kinase type I-beta regulatory subunit [KO:K04739]
114216134  PRKAR1A; cAMP-dependent protein kinase type I-alpha regulatory subunit [KO:K04739]
114225055  PRKAR2A; cAMP-dependent protein kinase type II-alpha regulatory subunit [KO:K04739]
114220866  PRKAR2B; cAMP-dependent protein kinase type II-beta regulatory subunit isoform X1 [KO:K04739]
114197074  LIPE; hormone-sensitive lipase isoform X1 [KO:K07188] [EC:3.1.1.79]
114213301  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
114207042  PRKCI; protein kinase C iota type [KO:K06069] [EC:2.7.11.13]
114225368  SLC2A4; solute carrier family 2, facilitated glucose transporter member 4 [KO:K07191]
114213776  FLOT2; flotillin-2 isoform X1 [KO:K07192]
114199267  FLOT1; flotillin-1 isoform X1 [KO:K07192]
114214362  SH2B2; SH2B adapter protein 2 isoform X1 [KO:K07193]
114205335  SORBS1; sorbin and SH3 domain-containing protein 1 isoform X1 [KO:K06086]
114211393  CBL; E3 ubiquitin-protein ligase CBL isoform X1 [KO:K04707] [EC:2.3.2.27]
114221055  CBLB; E3 ubiquitin-protein ligase CBL-B isoform X1 [KO:K22517] [EC:2.3.2.27]
114201951  CRKL; crk-like protein [KO:K04438]
114213901  CRK; adapter molecule crk isoform X1 [KO:K04438]
114198850  RAPGEF1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
114209759  RHOQ; rho-related GTP-binding protein RhoQ isoform X1 [KO:K07194]
114216192  EXOC7; exocyst complex component 7 isoform X1 [KO:K07195]
114226267  TRIP10; cdc42-interacting protein 4 isoform X1 [KO:K07196]
114198206  SREBF1; sterol regulatory element-binding protein 1 isoform X1 [KO:K07197]
114213809  ACACA; acetyl-CoA carboxylase 1 isoform X1 [KO:K11262] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
114219120  ACACB; acetyl-CoA carboxylase 2 isoform X1 [KO:K01946] [EC:6.4.1.2 6.3.4.14 2.1.3.15]
114216135  FASN; fatty acid synthase [KO:K00665] [EC:2.3.1.85]
114198647  PKLR; pyruvate kinase PKLR isoform X1 [KO:K12406] [EC:2.7.1.40]
114208634  HK3; hexokinase-3 isoform X1 [KO:K00844] [EC:2.7.1.1]
114218963  HK2; hexokinase-2 [KO:K00844] [EC:2.7.1.1]
114214114  HK1; hexokinase-1 [KO:K00844] [EC:2.7.1.1]
114214160  HKDC1; putative hexokinase HKDC1 [KO:K00844] [EC:2.7.1.1]
114202278  GCK; glucokinase isoform X1 [KO:K12407] [EC:2.7.1.2]
114212116  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
114204800  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
114219011  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
114203347  5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
114203348  5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
114200181  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
114225812  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
114197984  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
114210547  FOXO1; forkhead box protein O1 [KO:K07201]
114197341  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
114200576  G6PC3; glucose-6-phosphatase 3 isoform X1 [KO:K01084] [EC:3.1.3.9]
114201342  G6PC; glucose-6-phosphatase isoform X1 [KO:K01084] [EC:3.1.3.9]
114222728  G6PC2; glucose-6-phosphatase 2 [KO:K01084] [EC:3.1.3.9]
114223354  FBP1; fructose-1,6-bisphosphatase 1 [KO:K03841] [EC:3.1.3.11]
114223384  FBP2; fructose-1,6-bisphosphatase isozyme 2 [KO:K03841] [EC:3.1.3.11]
114217895  PCK2; phosphoenolpyruvate carboxykinase [GTP], mitochondrial isoform X1 [KO:K01596] [EC:4.1.1.32]
114197938  PCK1; phosphoenolpyruvate carboxykinase, cytosolic [GTP] isoform X1 [KO:K01596] [EC:4.1.1.32]
114213180  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
114216073  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
114220439  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
114213794  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
114212384  RPS6; 40S ribosomal protein S6 [KO:K02991]
114221076  40S ribosomal protein S6-like [KO:K02991]
114202233  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
114208602  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
114210795  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
114202586  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
114198841  TSC1; hamartin isoform X1 [KO:K07206]
114215501  TSC2; tuberin isoform X1 [KO:K07207]
114197985  RHEB; GTP-binding protein Rheb [KO:K07208]
114220328  BAD; bcl2-associated agonist of cell death [KO:K02158]
114198628  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
114226321  SHC2; SHC-transforming protein 2 [KO:K17447]
114219804  SHC3; SHC-transforming protein 3 [KO:K17448]
114206514  SHC4; SHC-transforming protein 4 [KO:K17449]
114216301  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
114211897  SOS2; son of sevenless homolog 2 [KO:K03099]
114219700  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
114201560  HRAS; GTPase HRas isoform X1 [KO:K02833]
114216565  KRAS; GTPase KRas isoform X1 [KO:K07827]
114207931  NRAS; GTPase NRas [KO:K07828]
114216801  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
114211580  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
114207692  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
114206298  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
114226331  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
114202353  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
114214409  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
114224173  MKNK1; MAP kinase-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K04372] [EC:2.7.11.1]
114226186  MKNK2; MAP kinase-interacting serine/threonine-protein kinase 2 isoform X1 [KO:K04372] [EC:2.7.11.1]
114216805  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
114219880  SOCS1; suppressor of cytokine signaling 1 [KO:K04694]
114211006  SOCS2; suppressor of cytokine signaling 2 [KO:K04695]
114216216  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
114207489  SOCS4; suppressor of cytokine signaling 4 [KO:K04697]
114225510  PTPN1; tyrosine-protein phosphatase non-receptor type 1 isoform X1 [KO:K05696] [EC:3.1.3.48]
114224307  PTPRF; receptor-type tyrosine-protein phosphatase F isoform X1 [KO:K05695] [EC:3.1.3.48]
114224898  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
114201201  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
114205461  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
114224851  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
114218704  INPPL1; phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 isoform X1 [KO:K15909] [EC:3.1.3.86]
114221763  INPP5A; type I inositol 1,4,5-trisphosphate 5-phosphatase isoform X1 [KO:K01106] [EC:3.1.3.56]
Compound
C00031  D-Glucose
C00369  Starch
C00575  3',5'-Cyclic AMP
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
PMID:14635525
  Authors
Ogawa W, Kasuga M.
  Title
[Mechanism of insulin action and diabetes mellitus]
  Journal
Seikagaku 75:1332-44 (2003)
Reference
PMID:11282018
  Authors
Bevan P.
  Title
Insulin signalling.
  Journal
J Cell Sci 114:1429-30 (2001)
Reference
PMID:12867054
  Authors
Kanzaki M, Pessin JE.
  Title
Insulin signaling: GLUT4 vesicles exit via the exocyst.
  Journal
Curr Biol 13:R574-6 (2003)
DOI:10.1016/S0960-9822(03)00478-0
Reference
PMID:10196204
  Authors
Moodie SA, Alleman-Sposeto J, Gustafson TA.
  Title
Identification of the APS protein as a novel insulin receptor substrate.
  Journal
J Biol Chem 274:11186-93 (1999)
DOI:10.1074/jbc.274.16.11186
Reference
PMID:15733744
  Authors
Gual P, Le Marchand-Brustel Y, Tanti JF.
  Title
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.
  Journal
Biochimie 87:99-109 (2005)
DOI:10.1016/j.biochi.2004.10.019
Reference
PMID:9748166
  Authors
Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ.
  Title
Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.
  Journal
Science 281:2042-5 (1998)
DOI:10.1126/science.281.5385.2042
Reference
PMID:11742412
  Authors
Saltiel AR, Kahn CR.
  Title
Insulin signalling and the regulation of glucose and lipid metabolism.
  Journal
Nature 414:799-806 (2001)
DOI:10.1038/414799a
Reference
PMID:15624019
  Authors
Inoki K, Corradetti MN, Guan KL.
  Title
Dysregulation of the TSC-mTOR pathway in human disease.
  Journal
Nat Genet 37:19-24 (2005)
DOI:10.1038/ng1494
Reference
PMID:16288289
  Authors
Ruggero D, Sonenberg N.
  Title
The Akt of translational control.
  Journal
Oncogene 24:7426-34 (2005)
DOI:10.1038/sj.onc.1209098
Reference
PMID:10567225
  Authors
Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR.
  Title
Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation.
  Journal
Biochem J 344 Pt 2:427-31 (1999)
DOI:10.1042/bj3440427
Reference
PMID:9445476
  Authors
Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G.
  Title
Phosphorylation and activation of p70s6k by PDK1.
  Journal
Science 279:707-10 (1998)
DOI:10.1126/science.279.5351.707
Reference
PMID:9609110
  Authors
Ogawa W, Matozaki T, Kasuga M.
  Title
Role of binding proteins to IRS-1 in insulin signalling.
  Journal
Mol Cell Biochem 182:13-22 (1998)
Reference
PMID:9609111
  Authors
Ceresa BP, Pessin JE.
  Title
Insulin regulation of the Ras activation/inactivation cycle.
  Journal
Mol Cell Biochem 182:23-9 (1998)
Reference
PMID:15229476
  Authors
Pollak MN, Schernhammer ES, Hankinson SE.
  Title
Insulin-like growth factors and neoplasia.
  Journal
Nat Rev Cancer 4:505-18 (2004)
DOI:10.1038/nrc1387
Reference
PMID:9346240
  Authors
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.
  Title
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.
  Journal
Cell 91:231-41 (1997)
DOI:10.1016/S0092-8674(00)80405-5
Reference
PMID:17344645
  Authors
Ferre P, Foufelle F
  Title
SREBP-1c transcription factor and lipid homeostasis: clinical perspective.
  Journal
Horm Res 68:72-82 (2007)
DOI:10.1159/000100426
Reference
PMID:18291668
  Authors
Raghow R, Yellaturu C, Deng X, Park EA, Elam MB
  Title
SREBPs: the crossroads of physiological and pathological lipid homeostasis.
  Journal
Trends Endocrinol Metab 19:65-73 (2008)
DOI:10.1016/j.tem.2007.10.009
Reference
PMID:11343120
  Authors
Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S
  Title
The lipid phosphatase SHIP2 controls insulin sensitivity.
  Journal
Nature 409:92-7 (2001)
DOI:10.1038/35051094
Reference
PMID:12791379
  Authors
Backers K, Blero D, Paternotte N, Zhang J, Erneux C
  Title
The termination of PI3K signalling by SHIP1 and SHIP2 inositol 5-phosphatases.
  Journal
Adv Enzyme Regul 43:15-28 (2003)
DOI:10.1016/S0065-2571(02)00043-2
Related
pathway
eju00010  Glycolysis / Gluconeogenesis
eju00061  Fatty acid biosynthesis
eju00500  Starch and sucrose metabolism
eju04010  MAPK signaling pathway
eju04070  Phosphatidylinositol signaling system
eju04210  Apoptosis
KO pathway
ko04910   
LinkDB

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